JP2005516027A - Viscoelastic combination for use during surgery - Google Patents

Abstract

  Disclosed are improved viscoelastic compositions useful in performing ophthalmic surgical procedures and particularly cataract treatments. This composition contains sodium hyaluronate and chondroitin sulfate and exhibits improved hydrodynamic properties. Hyaluronic acid or an ophthalmically acceptable salt has a molecular weight of 1,500,00 to 1,900,000 daltons and is present at a concentration of 1.0% to 2.0% (w / v). And chondroitin sulfate and its ophthalmically acceptable salts have a molecular weight of 20,000,00 to 100,000 daltons and are present in concentrations of 3% to 5% (w / v).

Description

(Field of Invention)
The invention described herein relates to the field of viscoelastic surgery, and exhibits viscoelastic properties that exhibit improved hydrodynamic properties for certain types of surgery (especially ophthalmic surgery). Related to a new combination of elastics.

(Background of the Invention)
Many known viscous or viscoelastic agents (hereinafter referred to as “drugs” or “viscoelastic agents”) used in ophthalmic surgery (eg, VISCOAT® (Alcon Laboratories, Inc.) ( Containing sodium hyaluronate and chondroitin sulfate); Provisc® (Alcon), Healon®, Healon® GV and Healon® 5 (Pharmacia & Upjohn), Amvisc® and Amvisc Plus® (Bausch & Lomb), and Vitrax® (Allergan), all of which contain essentially pure sodium hyaluronate (HA); and finally hydroxypropylmethyl Loin products (e.g., Cellugel (R) (Alcon)) of (HPMC) is). All these highly purified products are useful in certain ophthalmic surgical procedures (eg, cataract surgery). These products are used by skilled ophthalmologists for several surgical purposes, including maintaining intraocular space, protecting ocular tissues (especially corneal endothelial cells), and as an aid in the treatment of ocular tissues Is done. These drugs are generally viscous enough to allow a skilled surgeon to use these drugs for the intended surgical purpose, but this is through an acceptable caliber cannula. It is not viscous enough to make it difficult to squeeze out the drug.

  However, as suggested by many commercial products, not all viscoelastic agents best meet all surgical objectives. Due to these specific physical properties, certain viscoelastic agents are better adapted to certain aspects of the surgical procedure. For example, in cataract surgery, the relatively low molecular weight sodium hyaluronate and chondroitin sulfate combination found in VISCOAT® products can be used during capsulotomy or in maintaining the anterior chamber at any time during cataract treatment. And works well in adhesion or protection to tissues (especially corneal endothelium). However, due to its adhesive and coating properties, VISCOAT® products are less likely to be removed from the anterior chamber of the eye than other drugs. In addition, the VISCOAT® product can be used for tissue treatment to insert an intraocular lens (IOL) into the eye, although other specific agents are more suitable for performing this function. .

  A relatively high molecular weight sodium hyaluronate viscoelastic solution (e.g., Healon (R) product or PROVISC (R) product (Alcon Laboratories, Inc.)) having a functionally desirable viscosity is highly viscous There is, however, relatively non-adhesive for tissue that can be contacted during surgery. These properties make such viscoelastic solutions very suitable for use as a soft tool to gently treat delicate tissue during surgery. For example, these viscoelastic agents can be used to inflate capsule bags and to facilitate IOL insertion. These lack of stickiness and adhesion make it easy to remove them from the eye at the end of the surgery. However, sodium hyaluronate is not as effective as other drugs in protecting ocular tissue, especially during phacosuction.

  HPMC adheres well to ocular tissue and thus protects ocular tissue, but does not function in the same manner as e.g. VISCOAT (R) products in anterior chamber maintenance or sodium hyaluronate in tissue treatment. However, HPMC can be easily diluted with a wash solution for removal after IOL implantation. The removal of the viscous or viscoelastic agent at the end of the surgery generally affects preventing or reducing the severity of post-surgical intraocular pressure spikes.

  In general, viscous solutions containing relatively high molecular weight drugs (high molecular weight sodium hyaluronate) are more effective in maintaining intraocular space than less viscous solutions containing relatively low molecular weight drugs. Yes; however, high molecular weight drugs tend to be highly tacky and can be aspirated early from the surgical site. For example, this rapid suction can occur if the viscous solution comes into contact with the suction port of the lens ultrasound suction tip during the lens ultrasound suction procedure. Relatively low molecular weight products (due to their sticky characteristics that adhere to and protect the tissue) make it more difficult to remove from the surgical site.

  In recognition of the fact that each of the aforementioned drugs has certain advantages and disadvantages for a given surgical procedure, the use of multiple viscoelastic agents in a single surgical procedure is suggested. See U.S. Pat. No. 5,273,056. Multiple viscoelastic approaches have had some commercial success. For example, Pharmacia's Healon® series (each product contains a different molecular weight fraction of sodium hyaluronate), or Alcon's Duo Visc® products (Provis® and Viscoat®) Including both). Thus, there remains a need for a single viscoelastic agent that can adequately perform each function associated with a given surgical procedure. The composition of the present invention appears to meet this need.

  US patent application Ser. No. 09 / 857,543, assigned to the same person, discloses a viscoelastic agent designed for use in otic surgery. The composition disclosed therein is a formulation containing 1.6% high molecular weight sodium hyaluronate and 4% chondroitin sulfate. However, the specific molecular weight ranges of the present invention are not disclosed or suggested in that application, the contents of which are incorporated herein by reference. The application does not suggest the unexpectedly improved performance recognized by the present invention in ophthalmic surgery.

  US Pat. No. 6,051,560 discloses a combination of HA and chondroitin sulfate for use in ophthalmic surgery. A commercial embodiment of that patent is found in the Viscoat® product where 4% by weight of chondroitin sulfate having a molecular weight of about 22,500 daltons and more than 500,000 daltons according to package inserts. Contains 3% by weight sodium hyaluronate having a molecular weight. As noted above, commercially available products provide less than optimal performance at certain stages of a typical cataract surgical procedure. Quite unexpectedly, we offer all significantly improved performance compared to any product on the market by changing the molecular weight and concentration of polymer components in Viscoat®. It was discovered that it is possible to make a viscoelastic agent.

(Summary of the Invention)
The present invention relates to a specific combination of sodium hyaluronate and chondroitin sulfate, where this combination is a significant improvement to perform all the functions of a viscoelastic agent in ophthalmic surgical procedures (especially for cataract treatment). Is shown. During such treatment, the unique formulation of the components in the viscoelastic agent of the present invention achieves sufficient intraocular space maintenance and ocular tissue protection and at the same time facilitates removal at the end of ocular tissue treatment and procedure Make it possible. The object of the present invention is to provide a physician with the functional benefits of multiple drug systems without the costs and disadvantages associated with using multiple products / syringes during a single surgery. It is to provide a viscoelastic agent.

(Detailed description of the invention)
Viscoat® (Alcon) as described above has been commercially available for many years. Viscoat® formulations and methods for their manufacture are generally described in US Pat. No. 6,051,560, the entire contents of which are hereby incorporated by reference. Like all other stand-alone viscoelastic products currently on the market, the hydrodynamic properties of the Viscoat® material can be used in all steps of various surgical procedures (eg, cataract surgery). Ideally not suitable. The present invention relates to novel viscoelastic formulations having significantly altered hydrodynamic properties that are used in ophthalmic surgery (especially in conventional processes or stages of surgical removal of cataracts). Allows better performance.

  The composition of the present invention comprises about 1.0% to about 2.0% (w / v) of a medium molecular weight hyaluronate, preferably sodium hyaluronate, in an aqueous solution suitable for ophthalmic surgery. Contain with chondroitin sulfate at a concentration range of about 3% to about 5% (w / v). For the hyaluronic acid / hyaluronate (HA) component, the preferred molecular weight range is from about 1,500,000 to about 1,900,000 daltons, and preferably about 1,700,000 daltons. A preferred concentration range is about 1.5% to about 1.8% (w / v), and preferably about 1.6% (w / v). For the chondroitin sulfate (CS) component, the preferred molecular weight is from about 20,000 or 25,000 to about 100,000 daltons, more preferably from about 50,000 to about 90,000, most preferably about 80 1,000 Daltons. The chondroitin sulfate component of the compositions of the present invention can be obtained from Seikagaku (Tokyo, Japan) in the desired molecular weight range. The sodium hyaluronate component is, for example, Genzyme Corp. (Cambridge, MA) or can be obtained from methods known to those skilled in the art. The molecular weight determination of the HA component of the composition of the present invention is the average molecular weight as determined by gel permeation HPLC. The compositions of the present invention may be prepared by the method described in US Pat. No. 6,051,560 (previously incorporated by reference) and the method described in Example 1 below.

  Various viscoelastic formulations containing HA and CS were prepared according to Example 1 below. These formulations were then subjected to subjective assessment by a skilled surgeon and hydrodynamic assessment as described below.

Example 1
(Viscoelastic preparation)
A. HA raw material (sodium hyaluronate) was obtained aseptically.

  B. CS raw material (sodium chondroitin sulfate) was obtained non-sterilely.

CS was completely hydrated in buffer and sterile filtered with a 0.2μ filter.
C. After the aseptic process during mixing in two syringes connected by a Luer-Lok connector, the sterile HA material was hydrated in a sterile CS / buffer solution.

  D. After proper mixing and overnight hydration, a sterile, clear viscous solution was obtained and stored in the refrigerator for complete degassing.

  E. The viscous solution was then filtered with a 4.5μ filter under a pressure of 50 psi to obtain an essentially particulate free clear solution.

  (Example 2)

１つの好ましい実施形態（処方物Ｆ）および市販されている粘弾性製品を含む、試験した他の処方物の流体力学的性質を、図１に示す。図１より、処方物Ｆの粘性は、低い剪断速度で、Ｐｒｏｖｉｓｃの粘性およびＨｅａｌｏｎ ＧＶの粘性の間に独自に低下するが、意外なことに高い剪断速度で、Ｖｉｓｃｏａｔの粘性およびＰｒｏｖｉｓｃの粘性の間に低下することが示される。

The hydrodynamic properties of other formulations tested, including one preferred embodiment (Formulation F) and a commercially available viscoelastic product are shown in FIG. From FIG. 1, the viscosity of Formulation F falls uniquely between the Provis and Healon GV viscosities at low shear rates, but surprisingly at high shear rates, the Viscoat and Provis viscosities. It is shown to drop in between.

(Example 3)
Table 3 shows zero shear viscosity data for Formulation F and other formulations compared to commercial viscoelastic products.

図１に示されるデータと一致して、本発明の中程度分子量ＨＡ処方物（ＤおよびＦ）のゼロ剪断粘度は、ＶｉｓｃｏａｔおよびＰｒｏｖｉｓｃのゼロ剪断粘度より高かったが、Ｈｅａｌｏｎ−ＧＶのゼロ剪断粘度より顕著に低かった。

Consistent with the data shown in FIG. 1, the zero shear viscosity of the medium molecular weight HA formulations (D and F) of the present invention was higher than that of Viscoat and Provisc, but that of Healon-GV. It was significantly lower.

(Example 4)
Several physical parameters of the viscoelastic material were measured and well documented. Viscosity, pseudoplasticity (shear thinning), and molecular weight. Methods for measuring these stickiness are described in Poyer et al. Cataract Refract. Surg. 24: 1130-1135 (1998), the contents of which are incorporated herein by reference. Poyer et al. Describe the adhesion-dispersion index (CDI) of viscoelastic agents. This CDI is generally determined in the method shown in FIG. 2 and using the following materials and methods.

(Materials and methods)
(Materials and equipment)
Polypropylene test tubes (found bottom, 14 mL) were obtained from Becton Dickinson Labware and polypropylene pipette tips (model RT-20) were obtained from Rainin Instrument Co. Got more. Cell culture clusters (24 wells) were purchased from Costar. A Sartorius model 1612 balance was used for the gravimetric determination and a positive displacement pipette (Rainin model M1000) was used for moving the viscoelastic sample. Vacuum was applied with a Gast vacuum pump.

(Viscoelastic sample suction)
Polypropylene well inserts were cut from the bottom of 14 mL test tubes, weighed (W ₀ ), and inserted into wells of a 24-well cell culture cluster for fixed retention (FIG. 2). Polypropylene provides a non-adsorbing surface and minimizes the effects of suction due to potential adsorption forces from the container. A viscoelastic sample (0.5 mL) was dispensed into the insert using a positive displacement pipette and the insert (including the sample) was reweighed (W ₁ ).

The prepared reduced pressure was connected to a polypropylene pipette tip (inner diameter 0.5 mm) with flexible polyvinyl chloride tubing. The vacuum is applied to various levels expressed in gauges (5 inch Hg, 10 inch Hg, 15 inch Hg, 20 inch Hg, 24 inch Hg, and 28 inch Hg are 127 mm Hg, 254 mm Hg, 381 mm Hg, 508 mm Hg, At 610 mm Hg and 711 mm Hg), a new sample (in duplicate) was applied to the viscoelastic sample using each vacuum level. Depressurization was applied using a pipette tip secured to a ant slide clamp. The tip was lowered into the sample for 2 seconds of contact time. The tip position was fixed at an angle of 80 degrees from the horizontal plane of the sample and the bottom of the insert blocked the tip obstruction. After each sample was aspirated, all inserts were weighed again (W ₂ ).

(Data analysis and statistical analysis)
The proportion of aspirated viscoelastic sample was calculated as follows:
Aspiration rate = (W ₁ −W ₂ ) / (W ₁ −W ₀ ) × 100%
Data was plotted as aspiration rate versus vacuum. The slope of the steepest part of each viscoelastic curve (based on the two steepest points of the curve) was compared to statistical significance using covariance analysis (SAS Institute, Inc.). Each slope value represents the CDI of a particular viscoelastic agent (rate aspirated / 100 mm Hg vacuum).

  The degradation point of the viscoelastic agent indicates the level of decompression at the beginning of the bolus removal of the drug. Bolus removal (for degradation point purposes) is defined as more than 25% of the sample is removed by a single vacuum level. The degradation point was determined using the ratio of the suction curve to the vacuum curve. Dispersive viscoelastic drugs have a low degradation point, and adhesive compositions tend to have a relatively high degradation point (indicating rapid bolus removal).

  The viscosity and CDI of the viscoelastic composition was determined using the method described above.

本発明の中程度分子量ＨＡ処方物（表４のＳＯＶＤを示す）は、９〜１５の範囲に渡るＣＤＩを有する。これらのＳＯＶＤ処方物中のヒアルロン酸ナトリウムの分子量は、１，６００，０００〜１，７００，０００ダルトンの範囲に渡る。ＳＯＶＤ ＣＤＩ値は、ＶｉｓｃｏａｔのＣＤＩより有意に高く、Ｐｒｏｖｉｓｃ、ＨｅａｌｏｎおよびＨｅａｌｏｎ−ＧＶのＣＤＩより有意に低い。

The medium molecular weight HA formulation of the present invention (showing SOVD in Table 4) has a CDI ranging from 9-15. The molecular weight of sodium hyaluronate in these SOVD formulations ranges from 1,600,000 to 1,700,000 daltons. SOVD CDI values are significantly higher than Viscoat CDI and significantly lower than CDI of Provisc, Healon and Healon-GV.

  (Example 5)

本発明の好ましい組成物は、前区手術における外科用補助として使用する眼球内を意図とした粘弾性ポリマー溶液である。その溶液は、生理学的緩衝液中に溶解したヒアルロン酸ナトリウム（ＨＡ）（１．６％の濃度で）およびコンドロイチン硫酸ナトリウム（ＣＳ）（４％の濃度で）の中程度分子量画分からなる。その溶液は、眼房水と類似した浸透圧およびｐＨを有する。ＨＡは、１，６００，０００〜１，７００，０００ダルトンの平均分子量を有し、そしてＧｅｎｚｙｍｅ（Ｃａｍｂｒｉｄｇｅ，ＭＡ）より入手された。好ましい処方物は、少なくとも２５０〜３５０Ｐａ．ｓ．（眼房水より２５０，０００〜３５０，０００倍高い）の粘度を有する。免疫原性の徴候がないことがヒトにおいて機能させたＨＡおよびＣＳについての以前の研究において報告された。ウサギモデルにおける臨床治療前の研究において、この好ましい実施形態は、水晶体超音波吸引手術間の眼において残存することにより、水晶体超音波吸引術間に前眼房ドームの維持することを見出された。適切なドーム維持は、角膜内皮の効果的な保護に不可欠である。市販の粘弾性製品（Ｈｅａｌｏｎ−ＧＶおよびＨｅａｌｏｎ−５）との比較において、本発明の組成物は、水晶体処置の間、より深い前眼房を形成かつ維持し、その結果、角膜内皮および他の組織に対する最小限の外傷により、眼内の安全を可能にし、そして調節される処置を可能にした。Ｖｉｓｃｏａｔとの比較において、本発明の組成物は、水晶体処置後、洗浄／吸引（Ｉ／Ａ）処置の間の除去が容易であり、そして手術の間、きれいな視野を形成かつ維持した。本発明の組成物は、カニューレによって出す場合、粘性がかなり減少するため、注入が容易であが、注入後すぐにその高い粘性状態が戻る。臨床治療前の安全性の予備的結果は、本発明の組成物は、Ｈｅａｌｏｎとの比較において、眼内組織に対して非炎症性であり、受容可能なＩＯＰプロフィールを有していることを示す。

A preferred composition of the present invention is a viscoelastic polymer solution intended for intraocular use as a surgical aid in anterior segment surgery. The solution consists of a medium molecular weight fraction of sodium hyaluronate (HA) (at a concentration of 1.6%) and sodium chondroitin sulfate (CS) (at a concentration of 4%) dissolved in physiological buffer. The solution has an osmotic pressure and pH similar to aqueous humor. HA has an average molecular weight of 1,600,000 to 1,700,000 daltons and was obtained from Genzyme (Cambridge, MA). Preferred formulations are at least 250-350 Pa.s. s. (250,000-350,000 times higher than aqueous humor). The absence of signs of immunogenicity has been reported in previous studies on HA and CS functioning in humans. In a preclinical study in a rabbit model, this preferred embodiment was found to maintain the anterior chamber dome during phacoemulsification by remaining in the eye during phacosurgery. . Proper dome maintenance is essential for effective protection of the corneal endothelium. In comparison to commercially available viscoelastic products (Healon-GV and Healon-5), the composition of the present invention forms and maintains a deeper anterior chamber during lens treatment, resulting in corneal endothelium and other Minimal trauma to the tissue allowed intraocular safety and allowed for a regulated procedure. In comparison to Viscoat, the composition of the present invention was easy to remove during irrigation / aspiration (I / A) treatment after lens treatment and formed and maintained a clean field during surgery. The composition of the present invention, when dispensed by a cannula, is much easier to inject because of its considerably reduced viscosity, but returns to its highly viscous state soon after injection. Pre-clinical safety safety results show that the composition of the present invention is non-inflammatory to intraocular tissues and has an acceptable IOP profile compared to Healon .

  Those skilled in the art will also recognize that preferred compositions of the present invention are also assigned to commonly assigned US patent application 10 / 082,743 (use of a mixture of sodium hyaluronate and chondroitin sulfate in the treatment of cartilage softening and osteoarthritis). To be particularly useful in the treatment of cartilage softening and osteoarthritis (especially grade I osteoarthritis and grade II osteoarthritis) by intraarticular injection as described in . The contents of the above applications are incorporated herein by reference as reference.

  Those skilled in the art will similarly appreciate that the compositions and methods of the present invention have utility in a variety of treatments, particularly drug delivery, cosmetic surgery and reconstruction surgery. The present invention is particularly useful for gene therapy of antifibrotic drugs, antibiotics, steroidal and non-steroidal anti-inflammatory drugs, anesthetics, analgesics and other drugs, or diseased or damaged tissue in need thereof. Best suited. Cosmetically, these compositions can be injected to reduce wrinkles and treat dilated serpentine veins. For the treatment of dermal lines or wrinkles, these compositions are used as muscular relaxants (eg BOTOX® (Allergan, Inc., Irvine CA, USA), botulinum toxin type A, ) And can be injected subcutaneously in a conventional manner. The presently disclosed compositions and methods also require any tissue separation or stabilization and any environment where complications (typically resulting from tissue fibrosis and / or tissue adhesions after surgery) are possible. Can be used. They are particularly useful in nasal, spinal, cardiovascular, orthopedic and orthodontic surgical procedures that are otherwise prone to such complications It is. One skilled in the art will appreciate that the preferred retention characteristics of a viscoelastic agent will depend on the type of treatment being used.

  As used herein, the term “ophthalmically acceptable” when used in the described salt or vehicle, in any conventional sense, is any salt suitable for administration to the patient's eye or Means vehicle, and means that there is no significant risk of adverse health effects, especially during surgery. Most preferred are the sodium salt of hyaluronic acid and chondroitin sulfate, and an aqueous vehicle.

  The present invention will be described with respect to certain preferred embodiments by reference; however, the present invention may be embodied in other specific forms or variations thereof without departing from its spirit or central characteristics. Should be understood. Accordingly, the foregoing embodiments are considered in all respects to be illustrative and not restrictive, and the scope of the invention is indicated by the appended claims rather than the foregoing description.

FIG. 1 is a graph showing the hydrodynamic properties of an embodiment of the present invention along with the hydrodynamic properties of other viscoelastic formulations. FIG. 2 is a diagram illustrating a preferred method for determining adhesion-dispersion.

Claims (6)

A sterile, water-soluble viscoelastic composition for use during ophthalmic surgical procedures, wherein the composition is a combination of hyaluronic acid and chondroitin sulfate in an ophthalmically acceptable vehicle, or ophthalmic Wherein the hyaluronic acid or the ophthalmically acceptable salt thereof has a molecular weight of 1,500,000 to 1,900,000 daltons; Present in a concentration of 0% to 2.0% (w / v); and the chondroitin sulfate or the ophthalmically acceptable salt thereof has a molecular weight of 20,000 to 100,000 daltons and 3 A composition present at a concentration of% to 5% (w / v). The composition of claim 1, wherein the composition contains sodium hyaluronate at a concentration of 1.5% to 1.8% (w / v). The composition of claim 2, wherein the sodium hyaluronate has a molecular weight of 1,600,000 to 1,700,000 daltons. The sodium hyaluronate is present at a concentration of 1.6% (w / v) and the chondroitin sulfate or the ophthalmically acceptable salt thereof has a molecular weight of 50,000-90,000 daltons; 4. A composition according to claim 3 present in a concentration of 4% (w / v). The composition is:
Monobasic sodium phosphate at 0.045% (w / v);
Dibasic sodium phosphate at 0.2% (w / v); and NaCl at 0.31% (w / v)
The composition according to claim 4, further comprising: A method for performing cataract surgery on the eye, the method comprising administering to the eye a tissue stabilizing effective amount of the composition of any of claims 1-5.

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